Abstract 6718: Exploiting metabolic vulnerabilities of pediatric rhabdomyosarcoma with novelnicotinamide phosphoribosyltransferase (NAMPT) inhibitor OT-82
Authors: Grace McKay-Corkum, Victor J. Collins, Choh Yeung, Takeshi Ito, Sameer H. Issaq, Arnulfo Mendoza, Kazutoshi Yamamoto, Murali Cherukuri, Len Neckers, Christine M. Heske
Journal: Cancer Research (2023)

Abstract Purpose: A hallmark of cancer cells is altered metabolism. Therapeutically, these alterations may be exploited by targeting metabolic vulnerabilities specific to cancer cells. Efficient production of NAD through the NAD salvage pathway is one such potential vulnerability, as some tumor cells demonstrate a high need for rapid NAD turnover. Nicotinamide phosphoribosyltransferase (NAMPT) is the pharmacologically targetable rate-limiting enzyme in this pathway. We report on the effect of targeting NAMPT in models of pediatric rhabdomyosarcoma (RMS), a cancer for which novel therapeutics remain an unmet need. Experimental Procedures: The relative sensitivity of RMS cell lines to NAMPT inhibitors was first compared to NAMPT inhibitor sensitivity of other cancer cell lines using viability assays. A panel of ten molecularly diverse RMS cell lines was used for the remainder of the evaluations. In vitro activity of NAMPT inhibition was evaluated using assays of proliferation and cell death. Measurements of NAD and functional assessment of NAD-dependent processes, such as glucose metabolism, were used to study the mechanistic activity of NAMPT inhibition in these models. In vivo studies included assessments of toxicity, efficacy, and mechanism of action of a clinical NAMPT inhibitor, OT-82, in four orthotopic RMS models. Results: RMS cells showed striking sensitivity to NAMPT inhibition with IC-50 values in the low nanomolar range. In vitro, NAMPT inhibition resulted in NAD depletion and impaired cellular proliferation. Effects on glucose metabolism included decreases in glycolytic activity and glycolytic capacity in all cell lines tested, as well as decreased oxidative phosphorylation in a subset of cell lines. The majority of cell lines exhibited ATP depletion and irreversible necrotic cell death. Apoptotic cell death was not observed. In vivo, the effects of OT-82 treatment delivered on the human clinical schedule replicated those seen in vitro, including loss of glycolytic activity as measured using hyperpolarized 13C MRI spectroscopy. In all four xenograft models, complete tumor regressions were observed at multiple doses and with minimal toxicity. Conclusions: NAMPT inhibition with OT-82 was highly effective in decreasing RMS proliferation and impairing glucose metabolism both in vitro and in vivo. Given these results, there is a critical need for further clinical study of this class of agents for RMS. Citation Format: Grace McKay-Corkum, Victor J. Collins, Choh Yeung, Takeshi Ito, Sameer H. Issaq, Arnulfo Mendoza, Kazutoshi Yamamoto, Murali Cherukuri, Len Neckers, Christine M. Heske. Exploiting metabolic vulnerabilities of pediatric rhabdomyosarcoma with novelnicotinamide phosphoribosyltransferase (NAMPT) inhibitor OT-82 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6718.